Methods and Devices for Sonographic Imaging

ABSTRACT

The present invention comprises methods and devices for providing contrast medium for sonography of structures such as ducts and cavities. The invention provides for creation of detectable acoustic variations between two generated phases of a gas and a liquid to make a contrast medium. Sonography is the primary means of imaging but other conventional detection means may also be employed with the present invention.

TECHNICAL FIELD

The present invention relates to methods and devices for sonographicimaging of organs, ducts and cavities. In particular, methods anddevices of the present invention use detectable acoustic variations ofalternating patterns of a gas phase and a liquid phase traversing apassage.

BACKGROUND OF THE INVENTION

Non-surgical diagnostic procedures for examining body ducts andcavities, in particular the uterus and Fallopian tubes, are well known.One procedure, known as hysterosalpingography, employs contrast agentsand diagnostic fluoroscopic imaging techniques for viewing the uterusand Fallopian tubes. A safer, cheaper and easier method ishysterosonosalpingography, where ultrasound is utilized as the imagingmodality. Ultrasound imaging also allows for evaluation of the uterinecavity using saline as a method of choice without assessment ofFallopian tube patency. Tubal patency and tubal occlusion can beassessed only under ideal sonographic conditions, limiting itsusefulness clinically. Currently, no contrast agent indicated forcontrast enhancement during ultrasound evaluation of the uterine cavityand Fallopian tubes is available in the U.S. Other ultrasound contrastagents are available for widespread use but are limited to use incardiac and vascular applications. Most of the currently availablevascular contrast agents are stabilized against dissolution andcoalescence by the presence of additional materials, such as an elasticsolid shell that enhances stability, or a surfactant or a combination oftwo or more surfactants. Contrast agents can improve the image qualityof sonography either by decreasing the reflectivity of the undesiredinterfaces or by increasing the backscattered echoes from the desiredregions. In the former approach, the contrast agents are taken orally,and for the latter effect, the agent is introduced vascularly. To passthrough the lung capillaries and enter into the systemic circulation,microbubbles within a vascular contrast agent should be less than 10microns in diameter (2 to 5 microns on average for most of the neweragents). Stability and persistence become major issues for such smallmicrobubbles and air bubbles in this size range persist in solution foronly a short time. Hence the gas bubbles have to be stabilized for theagent to persist long enough and survive pressure changes in the heartfor systemic vascular use. Therefore, availability of contrast agents,procedural challenges, particularly during preparation of the patientand the contrast materials, and cost are disadvantages associated withknown contrast media used sonographically.

Although conventional contrast agents function adequately, thedisadvantages inherent in the conventional agents create a need forbetter contrast agents. One disadvantage with currently used contrastagents is that they are very expensive and difficult for some physiciansto obtain. Another disadvantage is that conventional contrast agentsmust be shaken prior to injection to either mix the components or togenerate bubbles, thus making the entire diagnostic procedure cumbersomeand possibly somewhat subjective. A third disadvantage is that thecontrast agent composition has a very short shelf life due to itsunstable nature once it is prepared for use in a patient.

In view of these disadvantages, other solutions have been tried. Oneattempt to overcome these disadvantages is a contrast medium that ismade from air mixed with sterile solutions of saline. Air and saline canbe used in place of conventional contrast agents in sonographicinvestigations, due to the ultrasound reflective properties of lowdensity phases, i.e., gas, in liquids. Generally, microbubbles of a gasare formed in the liquid carrier.

Microbubbles in liquids have been used as contrast media previously.Microbubbles may be generated by such methods as syringe motions in aback and forth manner in combinations of air and dispersants, orultrasonic cavitation means. It is known that such microbubbles are onlystable for a short amount of time. Pre-formed microparticles usingtemporary or permanent polymeric films have been used to address theshort stability lifespan. Pressurized systems have been used to createmicrobubbles in solutions. The technique involves a means of generatinga focused jet of gas in order to aerate the fluids with microbubbles.Such microbubbules may coalesce if there is a lag time betweengeneration and application into the structure to be visualized, thusthese methods have used a high velocity flow of liquid. Thus,limitations to this method are that the microbubbles introduced into afluid may coalesce into a few large bubbles or one large air pocket, themicrobubbles formed must be stable long enough for visualization tooccur, and due to the instability of the microbubbles, it is difficultto create reproducible conditions for comparative visualizations.

Accordingly, devices and methods are needed for creating contrast agentsthat resolve the issues currently encountered. Particularly, methods anddevices are needed for visualization of organ structure and function,such as visualization of the uterus and Fallopian tubes.

SUMMARY

The present invention comprises methods and devices for making and usingcontrast agents. Methods of the present invention comprise use of adevice for generating a contrast agent that is used for sonographicallyobserving organs or bodily structures, for example, the uterus andFallopian tubes. The contrast agent device may comprise a containerassembly and optionally, a catheter assembly fluidly coupled to thecontainer assembly. A container assembly may comprise a first containerfor providing a solution of a liquid, such as saline, and a secondcontainer for providing a gas, such as air, and elements for creating analternating pattern of gas and fluid, which is delivered directly to theorgan or structure by the catheter assembly. A container assembly maycomprise one or more containers. A container assembly may compriseelements for providing the contained substance from a container to thecatheter.

Methods of the present invention comprise sonographically observing alocation of a body, such as a uterus and its associated Fallopian tubes,using the devices disclosed herein. Methods comprise placement of acatheter delivery end in close approximation to the structure to beobserved, and providing the fluid/gas mixture to the structure. Forexample, in a method of viewing a Fallopian tube, a delivery devicecomprising at least one catheter is placed within the uterus, and the atleast one catheter is provided through the delivery device and isextended to the cornua of the uterus and the delivery end of thecatheter is held in place, for example, by an end structure such as aballoon. Once the catheter(s) is in place, the liquid/gas mixture, thecontrast medium, is provided from the contrast agent device to thecatheter, and to the Fallopian tube(s). Sonographic visualization isbegun, and one or both of the Fallopian tubes is examined. Depending onthe delivery device used to provide the contrast agent, the Fallopiantubes may be examined simultaneously or sequentially. If visualizationof the entire uterus is desired, for example, after visualization of theFallopian tubes, the catheter(s) is withdrawn from the cornua, andretracted until the end structure of a single catheter is in place atthe entrance to the uterus. The end structure, such as a balloon, isenlarged to provide a liquid seal of the uterus and the liquid/gascontrast agent is introduced into the uterus. Sonographic visualizationis begun and may be continued until a sufficient amount of theliquid/gas contrast agent is within the uterus.

Bodily structures of humans or animals, or inanimate objects can beeasily observed with the contrast agents of the present invention.Providing the contrast agent directly to the structure to be observedwith a catheter assembly aids in maintaining the structure of the gaswithin the liquid of the liquid/gas mixture. The methods of the presentinvention aid in the reproducibility of the methods of visualization andcomparative results therefrom.

DESCRIPTION OF FIGURES

FIG. 1 is a schematic of an exemplary embodiment of the presentinvention.

FIG. 2 is a schematic of an exemplary embodiment of the presentinvention.

FIG. 3 is a schematic of an exemplary embodiment of the presentinvention

FIG. 4 is a schematic of an exemplary embodiment of the presentinvention.

FIG. 5 is a schematic of a pattern of a contrast material in a Fallopianduct.

DETAILED DESCRIPTION

The present invention comprises methods and devices for making and usingcontrast agents for ultrasound or sonography visualization ofstructures. Such structures may be present in the bodies of humans oranimals, or may be inanimate structures. As discussed herein, themethods and devices are used for ultrasound visualization of a uterusand one or more Fallopian tubes of a mammal. It is to be understood thatthe methods and devices are not limited to this application, but can beused in visualization of ducts or structures, whether in living beingsor inanimate structures.

The present invention comprises devices for making a contrast mediumcomposition. As used herein, contrast agent and contrast medium mean acomposition that is visible by ultrasound methods, referred to assonography, and the terms may be used interchangeably. Methods of thepresent invention comprise use of a contrast agent device for generatinga contrast agent that is useful for sonographically observing organs orbodily structures, for example, the uterus and Fallopian tubes.

A contrast agent device comprises a container assembly and optionally, acatheter assembly fluidly coupled to the container assembly. A containerassembly may comprise at least one container for a fluid. A fluidcomprises a liquid or a gas. A container assembly may comprise a firstcontainer for a liquid, such as saline, and a second container for agas, such as air, and elements for creating an alternating pattern ofgas and fluid. A container assembly may comprise elements for providingthe contained fluid from a container to the catheter assembly. Thecontainer may comprise one or more outlets through which the fluid, suchas gas or liquid, exits the container, or the outlet may be used toprovide a fluid, either liquid or gas into the container. The containerassembly may comprise a component for providing force upon the fluidcontained within the container. For example, a container may be asyringe, and the component for providing force upon the fluid is asyringe plunger. The container assembly may comprise a component foractivating the component for providing force. For example, the containermay be a syringe, the component for providing force upon the containedfluid is a syringe plunger, and the component for activating the plungermay be a pump, or the hand of an operator.

The container assembly may further comprise fluid connections betweenone or more containers and a contrast pattern generating chamber. Suchfluid connections include, but are not limited to, tubing or needles.The container assembly may comprise a contrast pattern generatingchamber wherein the gas phase is introduced into the liquid phase andthe composition exiting the contrast pattern generating chamber ischaracterized by alternating phases of gas and liquid which form thepattern of the contrast medium composition. The container assembly mayprovide the contrast medium composition to a catheter assembly ordirectly to a structure to be visualized.

The container assembly may be in fluid connection with the catheterassembly. The catheter assembly may be a single or double lumencatheter. The catheter may comprise end structures, such as a balloon onthe delivery end of the catheter. The opposite end of the catheter, theattachment end, may have attachment elements for attaching the catheterto other elements, such as elements, such as a luer lock, to attach thecatheter to a container assembly. The catheter may comprise othercomponents such as a wire, sensors, cutting elements, retrieval elementssuch as clamps or pincers.

The present invention comprises devices for delivery of a contrastmedium to a structure. It is contemplated by an embodiment of thepresent invention that the contrast medium is provided by the catheterassembly substantially directly to a structure to be visualized. In anaspect of the invention, for example, in direct delivery to a fallopiantube, the amount of contrast medium used per each fallopian tubeevaluation may be small, such as less than 20 mL, less than 15 mL, less10 mL, less than 8 mL, less than 5 mL, less than 4 mL, less than 3 mL,less than 2 mL, less than 1 mL, less than 0.5 mL. The amount of contrastfluid used may be any amount that is sufficient to provide an accuratevisualization of the structure. The contrast fluid may substantiallyfill the structure visualized, or may only be present in particularlocations within the structure.

When the structure to be visualized is a Fallopian tube, any device thatprovides a catheter to the Fallopian tube may be used. A catheter may beconnected to the contrast media device comprising a container assemblydescribed herein. A particular device for providing a catheter to a bodystructure, such as a Fallopian tube, and that is useful in methods ofvisualizing a Fallopian tube is the device taught in U.S. patentapplication Ser. Nos. 11/065,886, 12/240,738, and 12/240,791, each ofwhich is herein incorporated in its entirety. In general theseapplications disclose a device comprising a housing and an introducershaft that is used to enter and traverse the uterus until the tip of theshaft approaches or touches the fundus of a uterus. Once the tip of theintroducer shaft is at the fundus of the uterus, the device may bestabilized. One or more catheters, such as two, are fed through theintroducer shaft and out into the uterine cavity. The placement of theintroducer shaft allows for the three dimensional alignment of thecatheter(s) with the cornua of the uterus. The catheter(s) is advanceduntil the delivery end(s) of the catheter(s) are in place in the cornua.An end structure, such as a balloon, is inflated or engaged, tostabilize the catheter(s) in place, and the end structure may prevent orminimize back-flow of materials exiting the catheter delivery end. Oncethe end structure is engaged, the catheter(s) is ready for delivery ofmaterials or other activities.

In a method of the present invention, the catheter placed by theintroducer shaft comprises the catheter assembly. The end of thecatheter opposite the delivery end, referred to herein as the proximalend or the attachment end, is attached to a container assembly of acontrast medium device of the present invention. The contrast medium isgenerated by the actions of the container assembly and the contrastmedium is provided into and through the catheter(s) and out into thecornua of the uterus and into to a Fallopian tube(s). Visualizationtechniques are initiated as the contrast medium enters the Fallopiantube(s) and if possible, flows through the tube(s) and out into theperitoneal cavity. If a tube is blocked, the medium will not flow. Thepressure built up by the blockage may or may not unseat the balloon torelieve pressure and the flow would then be directed into the uterus.

If the device providing the catheter uses only one catheter, thenvisualization of one Fallopian tube occurs, followed by readjustment ofthe device, such as rotation of the introducer shaft, as taught in thecited patent applications, and the steps are repeated to provide acontrast medium to the other Fallopian tube. The contrast mediumprovided may be any currently known contrast medium that may be providedthrough a catheter to a location.

Methods of the present invention comprise making a contrast medium. Acontrast medium device of the present invention is used to make acontrast medium. For example, a contrast medium device comprising onecontainer for fluid may comprise a container comprising a flexibleporous material contained within the container. An example wherein thecontainer is a syringe body is described, such as one shown in FIG. 4.The present invention is not limited to this design, but contemplatesother containers that would function in similar ways. The syringe issubstantially filled with a flexible porous material. The flexibleporous material includes, but is not limited to, strips or pieces ofwoven or nonwoven material, an open-celled material, such as a sponge,or fragments of a sponge, or any material that would contain a gas andrelease the gas when acted upon, such as by compression forces. Forexample, the flexible, porous material is an open-celled sponge. Thesponge is placed in the container and a liquid is added, but the liquiddoes not displace all of the air in the sponge. The syringe plunger isapplied to the large open end of the syringe and the other end of thesyringe is in fluid connection with the catheter assembly. As theplunger is depressed into the syringe, the sponge is compressed and theair is forced out into the liquid, creating bubbles. The bubbles andfluid enter the catheter and transit the catheter to the structure.Visualization of the structure is then possible. See FIG. 5 for anillustration of visualization of a Fallopian tube.

The present invention comprises contrast medium devices comprising morethan one container. For example, the contrast medium device may comprisetwo containers, such as one shown in FIG. 1, an example wherein thecontainers comprise a syringe body. The present invention is not limitedto this design, but contemplates other containers that would function insimilar ways. One of the containers, which may be a pre-filled syringe,contains a liquid. The liquid may be any of those disclosed herein, suchas saline or water, or known contrast agent fluids. A second container,which may be a pre-filled syringe, contains a gas. The gas may be any ofthose disclosed herein, such as air, carbon dioxide, oxygen, nitrogen orhalocarbon compound gases, other gases, or known contrast agent gases.The plungers of the two syringes are depressed simultaneously eithermanually or mechanically and the mixture of the gas and liquid form analternating pattern of gas phase and liquid phase, which is a contrastmedium. The contrast medium then enters and transits the attachedcatheter and exits into the structure, such as the Fallopian tube.Visualization of the structure is possible by ultrasound techniques.

Compositions of the present invention comprise a contrast medium madeusing the methods taught herein. A contrast medium of the presentinvention comprises a gas phase within a liquid carrier. The gas phasemay be a bubble or may be a liquid-free, gas-filled area adjacent to aliquid phase area, and the alternating gas-filled area and liquid areamay repeat multiple times. The sizes of the gas-filled areas or theliquid filled areas may be uniform in size or not. The present inventioncontemplates providing a contrast medium in reduced volumes, compared toamounts currently used which may be 20 mL or more, and providing thecontrast medium substantially in or very near the structure to bevisualized (i.e. Fallopian tube). The present invention controls theamount of gas and liquid used in combination to form the mixedgas/liquid composition, which enters the structure. The pattern of thecontrast medium composition can range from predominantly a gas (air orother gas) phase to predominantly a liquid (saline or other liquid)phase and can be provided in a regular pattern or in an irregularpattern. The ratios of the gas to liquid may be determined by the sizeof the respective syringe. The larger the air syringe the greater theair segment in the pattern of the composition. The use of a porousstructure may create a more random or irregular pattern. The amount ofcontrast medium delivered may be controlled by the amount of syringeplunger displacement.

A composition of the present invention may comprise a liquid and a gas,and optionally, surfactants, emulsifiers, or other stabilizing agents.The liquid, which may be seen as a carrier of the gas phase, may be anyliquid that is substantially free of solids and flows at normal orbodily temperatures. For example, the liquid may be water orphysiologically acceptable aqueous solutions including, but not limitedto, physiological electrolyte solutions, physiological saline solutions,Ringer's solution or aqueous solutions of sodium chloride, calciumchloride, sodium bicarbonate, sodium citrate, sodium acetate, or sodiumtartrate, glucose solutions, or solutions or mono- or polyhydricalcohol, e.g., ethanol, n-butanol, ethylene glycol,polyvinylpyrrolidone, or mixtures or combinations of these. Further, theliquid carrier may comprise physiologically acceptable non-aqueoussolutions, including, but not limited to, anhydrous or substantiallyanhydrous carrier liquids, alcohols, glycols, polyglycols, syntheticperfluoranated hydrocarbons, or in mixtures or combination with othernon-aqueous or aqueous liquids.

The contrast media compositions of the present invention may comprisesurfactants or compounds that stabilize the gas-liquid interface.Surfactant composition may be useful when the contrast medium isprovided to a structure that is larger than the catheter size used totransmit the contrast medium. Surfactants include tensides, such aslecithins; esters and ethers of fatty acids and fatty alcohols withpolyoxyethylene and polyoxyethylated polyols like sorbitol, glycols andglycerol, cholesterol; and polyoxy-ethylene-polyoxypropylene polymers,viscosity raising and stabilizing compounds, mono- and polysaccharides(glucose, lactose, sucrose, dextran, sorbitol); polyols, e.g., glycerol,polyglycols; and polypeptides like proteins, gelatin, oxypolygelatin,plasma protein, amphipathic compounds capable of forming stable films inthe presence of water and gases, such as the lecithins(phosphatidyl-choline) and other phospholipids, inter alia phosphatidicacid (PA), phosphatidylinositol, phosphatidylethanolamine (PE),phosphatidylserine (PS), phosphatidylglycerol (PG), cardiolipin (CL),sphingomyelins, the plasmogens, the cerebrosides, natural lecithins,such as egg lecithin or soya bean lecithin, or synthetic lecithins suchas saturated synthetic lecithins, for example,dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine ordistearoylphosphatidylcholine or unsaturated synthetic lecithins, suchas dioleylphosphatidylcholine or dilinoleylphosphatidylcholine, freefatty acids, esters of fatty acids with polyoxyalkylene compounds likepolyoxypropylene glycol and polyoxyalkylene glycol; ethers of fattyalcohols with polyoxyalkylene glycols; esters of fatty acids withpolyoxyalklated sorbitan; soaps; glycerol-polyalkylene stearate;glycerol-polyoxyethylene ricinoleate; homo- and copolymers ofpolyalkylene glycols; polyethoxylated soya-oil and castor oil as well ashydrogenated derivatives; ethers and esters of sucrose or othercarbohydrates with fatty acids, fatty alcohols, these being optionallypolyoxyalkylated; mono- di and triglycerides of saturated or unsaturatedfatty acids; glycerides of soya-oil and sucrose, block copolymers ofpolyoxypropylene and polyoxyethylene (poloxamers),polyoxyethylenesorbitans, sorbitol, glycerol-polyalkylene stearate,glycerolpolyoxyethylene ricinoleate, homo- and copolymers ofpolyalkylene glycols, soybean-oil as well as hydrogenated derivatives,ethers and esters of sucrose or other carbohydrates with fatty acids,fatty alcohols, glycerides of soya-oil, dextran, sucrose andcarbohydrates. Surfactants may be film forming and non-film forming andmay include polymerizable amphiphilic compounds of the type oflinoleyl-lecithins or polyethylene dodecanoate, phosphatidic acid,phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine,phosphatidylglycerol, phosphatidylinositol, cardiolipin, sphingomyelinand biocompatible and amphipathic compound capable of forming stablefilms in the presence of an aqueous phase and a gas, phospholipidsincluding phosphatidylcholine (PC) with both saturated and unsaturatedlipids; including phosphatidylcholine such asdioleylphosphatidylcholine; dimyristoylphosphatidylcholine (DMPC),dipentadecanoylphosphatidylcholine-, dilauroylphosphatidylcholine(DLPC); dipalmitoylphosphatidylcholine (DPPC);disteraoylphosphatidylcholine (DSPC); anddiarachidonylphosphatid-ylcholine (DAPC); phosphatidylethanolamines(PE), such as dioleylphosphatidylethanolamine,dipaimitoylphosphatidylethanolamine (DPPE) anddistearoylphosphatidylethanolamine (D SPE); phosphatidylserine (PS) suchas dipalmitoyl phosphatidylserine (DPPS), disteraoylphosphatidylserine(DSPS); phosphatidylglycerols (PG), such asdipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylglycerol(DSPG); and phosphatidylinositol.

The contrast medium compositions comprise gases, and any physiologicallyacceptable gas may be present in the compositions of the presentinvention. The term “gas” as used herein includes any substances(including mixtures) substantially in gaseous form at the normal humanbody (37° C.). Close to 200 different gases have been identified aspotentially useful for making ultrasound contrast agents, and includeoxygen, air, nitrogen, carbon dioxide or mixtures thereof, helium,argon, xenon, krypton, CHClF₂ or nitrous oxide, sulfur hexafluoride,tetrafluoromethane, chlorotrifluoromethane, dichlorodifluoro-methane,bromotrifluoromethane, bromochlorodifluoromethane,dibromodifluoromethane dichlorotetrafluoroethane,chloropentafluoroethane, hexafluoroethane, hexafluoropropylene,octafluoropropane, hexafluoro-butadiene, octafluoro-2-butene,octafluorocyclobutane, decafluorobutane, perfluorocyclopentane,dodecafluoropentane, fluorinated gases including materials which containat least one fluorine atom such as SF₆, freons (organic compoundscontaining one or more carbon atoms and fluorine, i.e. CF₄, C₂F₆, C₃F₈,C₄F₈, C₄F₁₀, CBrF₃, CCl₂F₂, C₂ClF₅ and CBrClF₂ and perfluorocarbons. Theterm perfluorocarbon refers to compounds containing only carbon andfluorine atoms and includes saturated, unsaturated, and cyclicperfluorocarbons such as perfluoroalkanes such as perfluoromethane,perfluoroethane, perfluoropropanes, perfluorobutanes (e.g.perfluoro-n-butane, optionally in admixture with other isomers such asperfluoro-isobutane), perfluoropentanes, perfluorohexanes andperfluoroheptanes; perfluoroalkenes such as perfluoropropene,perfluorobutenes (e.g. perfluorobut-2ene) and perfluorobutadiene;perfluoroalkynes such as perfluorobut-2-yne; and perfluorocycloalkanessuch as perfluorocyclobutane, perfluoromethylcyclobutane,perfluorodimethylcyclobutanes, perfluorotrimethylcyclobutanes,perfluorocyclopentane, perfluoromethylcyclopentane,perfluorodimethylcyclopentanes, perfluorocyclohexane,perfluoromethylcyclohexane and perfluorocycloheptane.). The saturatedperfluorocarbons, which are usually preferred, have the formulaC_(n)F_(n+2), where n is from 1 to 12, preferably from 2 to 10, mostpreferably from 3 to 8 and even more preferably from 3 to 6. Suitableperfluorocarbons include, for example, CF₄, C₂F₆, C₃F₈ C₄F₈, C₄F₁₀,C₅F₁₂, C₆F₁₂, C₇F₁₄, C₈F₁₈, and C₉F₂₀.

The present invention comprises embodiments of a contrast medium device.A device may be two separable components; a container assembly and acatheter assembly that locates the fluid output of the catheter assemblynear or in the targeted duct or cavity. Alternatively, a contrast mediumdevice may be of a single, one-piece construction with a containerassembly adjoined to a catheter assembly. A contrast medium device maycomprise a container assembly, and optionally, a catheter assembly. Acontrast medium device may comprise a container assembly that provides acontrast medium comprising a gas phase and a liquid phase. The contrastmedium device may comprise a container assembly comprising a modifiedconventional multiple syringe pump, either a mechanical or a manualhandheld device capable of accepting variously sized syringes. Thesyringe outputs are directed into a mixing chamber or conduit where theappropriately created train of gas (i.e. air) and liquid (i.e. saline)are then driven into the input of a catheter assembly. Directed deliveryof the injected contrast media in the proximity or within the duct (i.e.Fallopian tube) will allow for sonography of the structure. The contrastmedium composition is provided directly to the fallopian tube, by whichis meant that the contrast medium composition is delivered only to thefallopian tube, or only to the fallopian tube first, and not by afilling of the uterus with a fluid and having that fluid overflow intothe fallopian tubes. Providing a composition directly to a structure ismeant herein to mean that the composition is provided at or near anopening of the structure to be assessed, so that the composition entersthe structure and does not flow into the structure from a remote site ofdelivery of a composition.

An aspect of the present invention comprises a contrast medium devicecomprising a container assembly comprising a contrast pattern generatingchamber having a diameter in a range of 0.3 to 1.8 ratio to the diameterof the structure to be visualized. The diameter of the contrast patterngenerating chamber may be in a ratio of 0.1 to 100 the diameter of thestructure to be visualized. The contrast pattern generating chamber mayhave a diameter ratio of 0.5 to 1 of the structure to be visualized, adiameter ratio of 1 to 1 of the structure to be visualized, a diameterratio of 1 to 1.5 of the structure to be visualized, a diameter ratio of1 to 2 of the structure to be visualized. An aspect of a contrast mediumdevice comprises a container assembly comprising a contrast patterngenerating chamber that has a diameter substantially equal to thediameter of the structure to be visualized, wherein the ratio of thediameters is 1.

The interfaces of the alternating gas and liquid phases must be presentin sufficient numbers if a duct, tube or structure is to be visualizedby this contrast medium, and both phases must be present in the viewingregion during the time of viewing. It is the presence of both phasestraversing the viewing region that provide the visualization contrast.For example, if only one phase (either liquid or gas) is visible in theviewing region at a given time, assessment difficult or impossible. Bythe creation of multiple interfaces between the two phases in thecontrast medium, observation of structure is possible due to the flow ofthe contrast medium comprising the interfaces of the phases.

An aspect of the present invention comprises contrast medium devicescomprising contrast pattern generating chambers having diameters similarin diameter to the structure being observed. For example, if gas phaseis created that is smaller than the diameter of the structure to beobserved, the gas will rise to the upper portion of the duct andcoalesce with another gas phase and fill the diameter of the structure.An aspect of the present invention comprises contrast medium devicescomprising contrast pattern generating chambers having diameters thatare either larger or smaller in diameter to the structure beingobserved. For example, if very small gas phases are created in thecontrast pattern generating chamber, the small gas phases can bemaintained in a larger diameter structure using dispersing agents,surfactants, or other similar acting components in the liquid or gasphase. Such small gas phases may be achieved by vibratory manipulationof the container assembly. The higher the frequency of the oscillations,the smaller the released gas phase bubbles.

A manual means of creating a contrast medium can be achieved by the useof a contrast medium device comprising a container assembly comprising asingle syringe and a porous substance, such as open cell foams, sponges,or woven or non-woven fabrics or fibers or combinations thereof. Thesyringe is charged with one or more of these substances in a looselyfitted fashion and the plunger is then replaced in the fully retractedposition. The contrast medium is then injected or otherwise fed or drawninto the syringe chamber containing the porous substance(s). Uponcontrolled depression of the syringe plunger, the fluid and air or othergas egresses in a manner similar to the dual syringe system describedabove. The catheter assembly delivers the contrast medium into thestructure being assessed.

A use of the devices disclosed herein is to deliver compositions to astructure to be visualized. Diagnostic or therapeutic treatments may beprovided to humans or animals by delivering diagnostic compositions,such as contrast medium compositions, or therapeutic compositionscomprising therapeutic agents to a structure by using the contrastmedium device and a catheter assembly as described herein. For example,therapeutic compositions may be provided to a Fallopian tube incombination with alternating phase interfaces provided by theintroduction of a gas to the composition, and for treatment of theFallopian tube may comprise methotrexate, hormones, fertility enhancingcompounds, fertility interfering compounds, motility enhancingcompounds, motility interfering compounds, compounds affecting thecilia/deciliation cycle, cilia growth enhancing or interferingcompounds, ovarian follicle treatment compounds, antibacterial,antimicrobial, antifungal, antiviral, antimycoplasmal, or antiparisitalcompounds, compounds that reduce inflammation or scar tissue formation,composition comprising one or more antibiotics, antimycoplasma agents,or antiviral compounds; compositions comprising mucoproteins,electrolytes or enzymes to enhance or inhibit fertility, progesterone,estrogen, adrenergic active compounds, noradrenergic active compounds,nonsteroidal anti-inflammatory drug, prostaglandins, other compoundsthat may treat or prevent conditions related to the fallopian tube,uterus, ovaries, or other organs or coverings reached by a compositionflowing from the cornua or ostia of a fallopian tube or combinationsthereof. Therapeutic compositions comprise hormones for fertility,fertility enhancing compounds, gametes, sperm, ova, combinations ofsperm and ova, one or more zygotes, or one or more embryos, orcombinations thereof. In methods where delivery of such diagnostic ortherapeutic compositions are provided by directly providing suchcompositions to structures, the compositions may further comprise theintermingling of a gas with the diagnostic or therapeutic composition,and the delivery of the diagnostic or therapeutic compositions may bemonitored by techniques such as ultrasound. A composition comprisingtherapeutic agents combined with the interfaces created by combining agas with the therapeutic composition using a contrast medium device ofthe present invention may provide both treatment and diagnosis of thecondition of a structure in one step of delivering the composition.Alternatively, the combined therapeutic agent composition withinterfaces from gas/liquid phases may be employed to limit or locate themedicament in the targeted structure with the support of sonographicimaging allowing for diagnosis and treatment to occur simultaneously orin sequence.

FIG. 1 presents a schematic of an embodiment of contrast medium device100 comprising container assembly 101, and shows a portion of a catheterassembly 102 in fluid connection with container assembly 101, forcreating alternating and repetitive interfaces of gas and liquid phases.The container assembly 100 may be coupled to a catheter assemblycomprising a catheter 1. The dimensions of a contrast pattern generatingchamber 3 and/or a catheter may have diameters so as to maintain thedistinct gas/liquid phases and thereby minimize coalescing of likephases. In some embodiments, diameters of the contrast generatingchamber and the catheter may range from about 0.5 mm to about 5.0 mm. Apressure relief valve 2 may minimize undue pressure build up in astructure, such as in a Fallopian tube, if the structure is blocked,such as if a Fallopian tube is not patent. Such valves may be used inline in other locations in the device (not shown) or embodiments mayhave no valves. It may also function as a secondary relief to an endstructure on a catheter, such as a balloon, when the catheter ispositioned in the entryway to the Fallopian tube, the cornua, and theend structure acts to hold the catheter in place.

The contrast pattern generating chamber 3 creates the phases withinterfaces between a liquid (e.g., saline) phase 14 and the gas (e.g.,air) phase 13. Formation of interfaces between gas and liquid phasesoccurs as the two media enter the contrast pattern generating chamberupon being advanced by dual syringe pump 7. A rubber septum 4 permits aneedle 9 to be inserted into contrast pattern generating chamber 3 withair tight sealing. A liquid phase is introduced into contrast patterngenerating chamber 3 through a connection 10, which may be tubing. Thegas or liquid may be provided from either container. Valves may be addedin line, such as inn order to prevent possible flow along the path ofleast resistance, a one-way check valve 12 may be positioned posteriorto needle 9. Preceding the check valve is an in-line aseptic filtrationdevice 5 of 0.2 or so micron porosity, such filters may be used in linefor either or both media. Embodiments of the present invention maycomprise devices that do not include such valves or filters. Syringe 11a as well as syringe 11 b may be pre-loaded with their respectivemedium, either liquid or gas, and placed and locked into dual syringepump 7. The syringe pump drive block 8 advances the respective gas andliquid syringe plungers 6 a and 6 b in a simultaneous fashion. Junction15 is formed between the contrast generating chamber and a catheter.Vibrator 16 is an optional element that is used to create vibrationsthrough needle 9 to create smaller phases, such as bubbles, of the phaseexiting needle 9, either gas or liquid.

An alternative embodiment comprises a dual pump where the drive blockcomprises two separate drivers for the two individual syringes. Thispermits the modification of the interface pattern, or the gas/liquidphases, to provide one phase in shorter or longer segments over theother. This could be accomplished by a slower (or faster) rate ofdelivery by one plunger over the other.

Needle 9 diameter may be somewhat smaller or slightly smaller than thediameter of the contrast pattern generating chamber to allow the phasedelivered through needle 9 to be affected by the other phase in thecontrast pattern generating chamber 3, so that the phase delivered byneedle 9 is dispersed in discrete amounts. For example, surface tensionof a liquid, delivered through needle 9, may cause a definite amount ofliquid to detach from the needle end and form a liquid phase within thegas in the contrast pattern generating chamber. For example, the needlegauge can range from about 10 to 30.

FIG. 2 is similar to FIG. 1 except that contrast medium device 200 has acontrast pattern generating chamber having a diameter larger than adelivery catheter. FIG. 2 is numbered similarly to FIG. 1, showingcontainer assembly 201 in fluid connection with catheter assembly 202.

FIG. 3 is similar to FIG. 1 except that contrast medium device 300 has acontrast pattern generating chamber having a diameter larger than adelivery catheter, and no needle 9 is present. , FIG. 3 is numberedsimilarly to FIG. 1, showing container assembly 301 in fluid connectionwith catheter assembly 302.

FIG. 4 is a schematic of an embodiment of a container assembly 200 usedfor creating and delivering an alternating gas/liquid contrast medium toa catheter assembly or similar device. The syringe 10 is packed with aporous substance 20. The porous substance 20 is partially saturated witha liquid 30. This may be achieved by withdrawal of the plunger 40, andsubmersing the syringe in a liquid, injection of liquid via the syringeopening 50 or other suitable means of placement of the liquid in theinterstices of the porous substance 20. For example, the poroussubstance may be provided in a wetted state, with the liquid alreadyassociated with the porous substance, prior to placement in thecontainer. The syringe opening 50 is properly coupled with or without anaseptic filtration component, to a catheter assembly or similar deliverycomponent to transfer the contrast medium to the desired site. Theplunger 40 is gradually advanced so that the liquid and gas phasesalternatively exit the syringe opening 50 to the catheter assembly andis delivered to the intended site to be imaged.

FIG. 5 is a schematic of visualization of a Fallopian tube using acontrast medium composition of the present invention, and a deliverydevice of U.S. patent application Ser. Nos. 12/240,738 and 12/240,791.Introducer shaft 60 is shown positioned in the uterus 120. The catheterassembly 70 is extended from introducer shaft 60 and delivery end of thecatheter 80 is in place in the cornua of the uterus. Contrast medium 130is present in Fallopian tube 90, and comprises contrast medium 130 witha fluid phase 100 and a gas phase 110.

Methods of the present invention comprise using a contrast medium toobserve structures via ultrasound techniques. The present inventioncomprises making a contrast medium using liquid and gas phases in apattern using a contrast medium device as described herein. The contrastmedium is delivered directly to or in the structure to be visualized bysonography. For example, if Fallopian tubes are to be examined, thecontrast medium is delivered to the uterine cornua or at the opening ofthe Fallopian tube by a catheter. In contrast, other known systemsrequire filling the entire uterus with a liquid, such as saline, andthen adding mixed gas/liquid composition to the saline-filled uterus andwaiting until the gas/liquid mixture reaches the Fallopian tubes.Procedural limitations exist with such a method in that it requirescharging the uterus with enough saline for distension before theintroduction of the air and saline to visualize the Fallopian passages,the air present in the uterus or tubes may create air pockets thatchange fluid flow, and the patient may need to be maneuvered to oddpositions for gas flow in a useful direction. The physician must performmultiple switching steps of a complex nature. The present invention maycomprise a single step process which uses a simple automated contrastmedium device or a handheld contrast medium devices.

With the present invention, the direct delivery of the contrast mediumcomprising a gas/liquid interface pattern from the contrast mediumdevice to the Fallopian tubes will confirm patency of the tubes by theunobstructed flow during visualization and does not result in anunnecessary buildup of material in the cul-de-sac. The delivery volumemay be confined to the potential volume of the Fallopian duct,approximately about 2 milliliters, for a single evaluation and maycomprise a greater amount to confirm the initial observations. Imaging aFallopian tube may comprise use of a combined fluid/gas phasecomposition of from about 0.5 mL to about 20 mL, from about 1 mL toabout 15 mL, from about 1 mL to about 5 mL, from about 1 mL to about 10mL, from about 10 mL to about 20 mL, from about 1 mL to about 3 mL, fromabout 15 mL to about 20 mL.

Tubal blockage may be evident by the lack of contrast medium mobilityalong the Fallopian tube into the peritoneal cavity. Ensuing pressurerelief may be provided by a relief valve in the device or by movement ofan end structure on the delivery catheter from its position in thecornua. A device of the present invention lends itself to beingautomated once the syringes have been inserted into the pumping systemor activation by manual delivery once syringes are inserted into orattached to a handheld device.

An embodiment of the present invention contemplates a contrast mediumdelivery device that does not require supplemental systems, such as aliquid reservoirs or valve control of the fluid flow on or attached tothe device. A simplified device and methods leads to a higher likelihoodof a successful procedure and outcome. Further, the present device isable to maintain the pattern of alternating phases for periods of timethat are useful for sonography. This permits the user the freedom toproperly locate structures and reposition the patient or structure, orcatheter during the procedure. Generally, there is no coalescing ofindividual phases. The pattern of gas/liquid phases or interfacescreated by the contrast medium device is visually observed at the onsetand each segment of media and rate of delivery can be controlled to suitthe needs of the user.

In passageways of structures where the volumes and diameters are large,such those with diameters greater than the dimensions found in Fallopiantubes, the two phases of gas and liquid may be maintained by additivesor surfactants, such as those disclosed herein. The contrast mediumdevice may comprise larger containers than the syringes shown herein.For example, one container may be used, and the container may contain aliquid that is foamed. The foam may be created by shaking, addingfoaming agents, by sonication or stirring. The foam may be transferredto the cavity to be imaged by transporting the foam from the containerassembly through a catheter assembly to the structure to be assessed. Itis apparent that other methods of creating the dispersion are possibleand can include mechanized means to do so. The phase created by thesemethods permits one to regulate the sizes of the resultant foam bycontrol of shaking or agitation as well as the types and concentrationsof the dispersants.

The methods of the present invention allow for assessment ofpassageways, such as the Fallopian tube and uterine cavity, byultrasound and provide a simple, safe and inexpensive outpatient method.Methods of the present invention comprise sonigraphically observing alocation of a body, such as a uterus and its associated Fallopian tubes,using the devices and compositions disclosed herein.

In general, the present invention comprises methods and devices forvisualizing structures, by providing contrast medium compositions to thestructure and visualization techniques such as ultrasound. Visualizationof the contrast medium in or around the structure provides informationto the viewer and such methods and devices can be used for diagnosis andtreatment of conditions related to the structure viewed. The methods anddevices of the present invention are useful for diagnosis and treatmentof conditions related to Fallopian tubes of humans and animals.

A contrast medium device of the present invention comprises a containerassembly comprising at least one container for containing a fluid, acomponent for moving a fluid from the container, components forconnecting the at least one container to the container assembly, andoptionally comprising a catheter assembly in fluid connection with thecontainer assembly. In embodiments of the invention, the container is asyringe and the component for moving a fluid from the container is asyringe plunger. Embodiments may further comprise a component foractivating the syringe plunger, and the component is a mechanical pumpor hand action. The devices may further comprise connecting elements tofluidly connect parts of the devices, valves, needles, filters,vibrators, pumps and other components.

Embodiments comprise devices where at least one container furthercomprises a porous substance and a gas. A porous substance may be anysubstance that can contain gas and liquid and release the gas and liquideasily upon compression or physical force upon the porous substance. Forexample, a porous substance may be a sponge, such as open cellpolyurethane sponge, that may be compressible. For example, a poroussubstance may be material that contains a gas and a liquid is rigid, butcollapses upon compression, to release the gas and liquid. A poroussubstance may be provided to a container in a dry state, wherein theporous substance contains gas, and a liquid may be added to thecontainer so that the porous substance contains both a gas and a liquid.Alternatively, the porous substance may be wet, containing both liquidand gas, and thus be provided to a container. More liquid may be addedto the container or not after insertion of the wetted porous substance.It is theorized that the porous substance comprises a gas within itspores and a liquid associated therewith the porous substance. The liquidand gas may be found within the pores or associated with the porousmaterial in an easily releasable fashion, such as by surface tension,hydrogen bonding or other weak bonding associations.

The liquids provided to containers or porous substances may furthercomprise a surfactant, emulsifier, other stabilizing agents, or otherdispersing agents. The liquids provided to containers or poroussubstances may further comprise liquids that are foamed. Liquids may befoamed by methods known in the art.

Embodiments of the present invention comprise contrast medium devicescomprise a container assembly comprising two containers and a patterncontrast generating chamber in fluid connection with the containers. Forexample, the containers may be syringes, each comprising a component formoving fluid from the container that is a syringe plunger. Suchembodiments may further comprising a component for activating thesyringe plungers and the component is a mechanical pump or hand action.In two container devices, one container contains a gas and the othercontainer contains a liquid. For example, where the containers aresyringes, one contains a gas and the other syringe contains a liquid. Inthe present invention, where two or more containers are used in adevice, the containers may be of the same or different size, volume,diameter, length or made from the same or different materials.

A method of the present invention comprising viewing structures usingultrasound techniques known to those skilled in the art. A method ofsonographic visualization of a structure comprises, creating a contrastmedium comprising alternating phases of a gas and a liquid in a contrastmedium device comprising at least one container; providing the contrastmedium to a catheter assembly, wherein the catheter assembly comprises acatheter delivery end positioned at or near a structure to bevisualized; delivering the contrast medium directly to the structure tobe visualized; and viewing the contrast medium in the structure byultrasound. A method of sonographic visualization of a structurecomprises observing a structure having a contrast medium of the presentinvention contained within it, or flowing through the structure. Methodsof the present invention comprise making a contrast medium comprisingadmixing a gas and liquid in a contrast medium device such thatalternating phases of gas and liquid, with visible interfaces betweenthe phases that form a visible pattern by ultrasound, are created toform a contrast medium composition.

Any structure that is viewable using ultrasound may be viewed using thecontrast medium compositions of the present invention, and contrastmedium compositions made by the contrast medium devices taught herein.For example, a structure to be visualized is at least one Fallopian tubeof a human or animal.

The contrast medium compositions of the present invention may be madewith a liquid that is flowable and forms a discrete liquid phase when incontact with a gas. The contrast medium liquid may comprise visualizableliquids or not. The contrast medium composition may further comprise atherapeutic composition. Therapeutic compositions comprise therapeuticagents including, but not limited to, methotrexate, hormones, fertilityenhancing compounds, fertility interfering compounds, motility enhancingcompounds, motility interfering compounds, compounds affecting thecilia/deciliation cycle, cilia growth enhancing or interferingcompounds, ovarian follicle treatment compounds, antibacterial,antimicrobial, antifungal, antiviral, antimycoplasmal, or antiparisitalcompounds, compounds that reduce inflammation or scar tissue formation,composition comprising one or more antibiotics, antimycoplasma agents,or antiviral compounds; compositions comprising mucoproteins,electrolytes or enzymes to enhance or inhibit fertility, progesterone,estrogen, adrenergic active compounds, noradrenergic active compounds,nonsteroidal anti-inflammatory drug, prostaglandins, other compoundsthat may treat or prevent conditions related to the fallopian tube,uterus, ovaries, or other organs or coverings reached by a compositionflowing from the cornua or ostia of a fallopian tube or any combinationthereof, or combinations thereof. Treatment compositions comprisehormones for fertility, fertility enhancing compounds, gametes, sperm,ova, combinations of sperm and ova, one or more zygotes, or one or moreembryos, or combinations thereof.

Methods of visualization of structures may comprise use of compositionsmade by a contrast medium device of the present invention. Inembodiments, the contrast medium device comprises a container containinga porous substance and a fluid. The porous substance further comprises agas, and the liquid may comprise a surfactant, emulsifier, otherstabilizing agents, or other dispersing agents. The liquid may befoamed.

Methods of the present invention comprise delivery of a contrast mediumcomposition of the present invention directly to the structure. Forexample, a contrast medium composition may be delivered directly to aFallopian tube. The composition may be delivered by a catheter and thecatheter may be provided to the location by devices known in the art andby those taught herein. For example, the catheter may be provided sothat the catheter delivery end is positioned in the cornua of a uterus.The contrast medium composition is provided through the catheter and outinto the opening of the Fallopian tube, and the composition flowsthrough the Fallopian tube, if possible. The contrast medium compositionis visible by ultrasound and the condition of the Fallopian tube can bedetermined by the visualization, diagnoses may be provided or treatmentto the Fallopian tube or other structures may be provided. For example,the patency or occlusion of at least one Fallopian tube is determinedwhen viewing the at least one Fallopian tube by ultrasound. Methods ofthe present invention comprise using small amounts of contrast mediumcomposition to assess or treat structures, such as a Fallopian tube, andthe amount of contrast medium to be provided to the structure is lessthan 20 mL for a single evaluation.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise.

All patents, patent applications and references included herein arespecifically incorporated by reference in their entireties.

It should be understood, of course, that the foregoing relates only topreferred embodiments of the present invention and that numerousmodifications or alterations may be made therein without departing fromthe spirit and the scope of the invention as set forth in thisdisclosure.

The present invention is further illustrated by the following examples,which are not to be construed in any way as imposing limitations uponthe scope thereof. On the contrary, it is to be clearly understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which, after reading the description herein, maysuggest themselves to those skilled in the art without departing fromthe spirit of the present invention and/or the scope of the appendedclaims.

EXAMPLES Example 1

Preparation of Contrast Medium with Dual Syringe Pump

A container assembly comprising a dual pump was made, as generallydepicted in FIG. 1, with two syringes, one 6cc and the other 20cc involume. The 6cc syringe was completely filled with saline and the 20ccwas filled with air. Sterile 0.2 μm filters (Sartorius Minisart orWhatman Syrfil-MF) were attached to the syringes, as sterile techniquewas desired. A 27 gauge, 3.5″ length spinal needle was used to inject agas phase into a fluid phase in the contrast pattern generating chamberto create the alternating air and liquid phase interfaces. A PICC-Natecatheter T-port extension and two lengths of extension tubing wereutilized in the set-up.

Variations of syringe ID, pump volume, pump rate and pump delay settingswere evaluated and yielded an acceptable contrast medium, as visualizedin a catheter assembly forward of the container assembly. The contrastmedium was delivered into clear PVC tubing that simulated the dimensionsof a Fallopian tube. The user could alter the pattern created with thegas and liquid phases by allowing for increased volumes of gas or liquidand the speed by which the contrast medium was delivered by adjustingthe settings on the pump. A fairly regular pattern of gas/liquid phaseinterfaces was created by the contrast medium device.

Example 2

Preparation of Contrast Medium with Handheld Dual Syringes

The assembly of Example 1 was followed using a housing to support thedual syringes. A block was placed behind the plunger of the 6cc syringecontaining saline to align with the plunger distance of the 20cc syringecontaining air. The creation of the contrast medium and its delivery toa catheter were controlled and manipulated by hand force on the plungersof the dual syringes as necessary to deliver the contrast medium intothe catheter. When the two plungers of the syringes were pushedsimultaneously, the pattern of the contrast medium was uniform, withsubstantially equal amounts of air and saline phases, alternating in thecatheter. When one plunger was pushed, followed by pushing of theplunger of the other syringe, the pattern was sometimes regular andsometimes irregular, depending on the activation of the individualplungers. Although the sizes of the individual segments of air andsaline phases were not uniform, the phases of liquid/air were repeatedsufficiently to view easily. The contrast medium was delivered intoclear PVC tubing that simulated the dimensions of the Fallopian tube.

Example 3

Preparation of Contrast Medium with Syringe Containing Porous Substance

A sterile Optipore scrubbing sponge was cut lengthwise in two equalparts. The plunger from a 60 cc syringe was removed and the spongehalves were inserted, one behind the other. The plunger was reinsertedin the syringe and depressed to the 15 cc mark. The syringe tip wassubmerged into a sterile container of saline and the plunger waswithdrawn to the 30 cc mark. The container assembly was now assembledand loaded. The container assembly was attached to a catheter assemblyand the plunger was depressed to create an air and saline composition, acontrast medium composition, for sonographic visualization. The contrastmedium was delivered into clear PVC tubing that simulated the dimensionsof the Fallopian tube. An irregular pattern or random pattern wasvisualized as the user controled the delivery of the contrast medium.Although the sizes of the individual segments of air and saline phaseswere not uniform, the phases of liquid/air were repeated sufficiently toview easily.

Example 4 Study of Contrast Medium Created by Dual Syringe Pump inSimulated Model

A contrast medium device of FIG. 1 and Example 1 was used to delivercontrast medium created by the device, made with saline as the liquidphase and air as the gas phase, to a channel sized to mimic the humanFallopian tubes in an ultrasound phantom model (purchased from BluePhantom, a division of Advanced Medical Technologies, LLC, Kirkland,Wash.). The delivery end of a catheter assembly was positioned in thesimulated Fallopian tube. The contrast medium device pump was activated,creating the contrast medium, and the contrast medium was delivered tothe model Fallopian tube and resembled the pattern shown in FIG. 5. Anultrasound machine (manufactured by GE Medical Systems, model: Voluson730Pro) was used to visualize the contrast medium created, whichtraveled in real-time down the channel or simulated Fallopian tube andthe gas/liquid phase contrast was visualized with the ultrasound probe.

Example 5 Study of Contrast Medium Created by Dual Syringe Pump in HumanSubjects

A contrast medium device of FIG. 1 and Example 1 was used to delivercontrast medium to human subjects' fallopian tubes. The contrast mediumcomposition was created by the device using saline as the liquid phaseand air as the gas phase, each traveling through an aseptic filter ofapproximately 0.2 microns in size to ensure sterility. The catheterassembly was provided to the human patients using a delivery system,described in U.S. patent application Ser. No. 11/065,886placed at thecornua of each subject. The contrast medium was delivered through thecatheter of the delivery system and was visualized using an ultrasoundinstrument (manufacturer: GE Medical Systems, Model: Logic 500). Tubalpatency was evidenced by contrast medium traversing the Fallopian tubesand exiting into the peritoneal cavity. This evaluation was conducted inreal-time with assessment of contrast medium flow evident upon properpositioning of the delivery system.

Example 6 Study of Contrast Medium Created by Syringe Containing PorousSubstance in Simulated Model

A contrast medium device like that shown in FIG. 4 and Example 3 wasused to deliver contrast medium created by the device, wherein salinewas the liquid phase and air was the gas phase, to a channel sized tomimic the human Fallopian tubes in an ultrasound phantom model(purchased from Blue Phantom, a division of Advanced MedicalTechnologies, LLC, Kirkland, Wash.). The porous substance used was ahighly porous polyurethane open cell foam designed for protectivepackaging material. A delivery end of a catheter assembly was positionedin the simulated Fallopian tube and the contrast medium device wasactivated by hand, creating a contrast medium that was more irregular inpattern than that shown in FIG. 5. An ultrasound machine (manufacturedby GE Medical Systems, model: Voluson 730Pro) was used to visualize thecontrast medium created, which traveled in real-time down the channel orsimulated Fallopian tube and the gas/liquid phase contrast mediumcomposition was visualized with the ultrasound probe.

Example 7 Study of Contrast Medium Created by Syringe Containing PorousSubstance in Human Subjects

A contrast medium device like that shown in FIG. 4 and Example 3 wasused to deliver contrast medium created by the device wherein saline wasthe liquid phase and air was the gas phase, to human subjects' Fallopiantubes by way of a catheter assembly incorporated in a delivery system asdescribed in U.S. patent application Ser. No. 11/065,886. The deliverydevice was placed in the uterus of a human subject and the delivery endof one or both catheters were in place in the cornua of the uterus. A60cc sterile syringe was packed with a 3×2″ sterile Optipore woundcleansing sponge (manufactured for ConvaTec, division of E. R. Squibb &Sons, LLC, Princeton, N.J.). The sponge was constructed of polyurethaneand was highly porous in nature. Saline was drawn into the syringe so asto fill the syringe, but not to remove the air trapped in the sponge.The syringe was attached to the attachment end of one or both cathetersof the delivery device. When the plunger of the syringe was depressed,the contrast medium was formed and was delivered through the catheterassembly, and out into the Fallopian tube(s). The contrast medium wasvisible under ultrasound (manufacturer: Philips, Model: HD3) Thisevaluation was conducted in real-time with assessment of contrast mediumflow evident upon proper positioning of the delivery system.

1.-24. (canceled)
 25. A method for determining patency of at least onefallopian tube of a mammal comprising, a) providing a gas-liquidcontrast medium composition comprising a liquid and a gas that is madeby a liquid and gas contrast medium-forming device comprising acontainer assembly comprising two containers having the same volume, afirst container for containing a gas and a second container forcontaining a liquid, two plungers, each disposed in a respectivecontainer, each for moving a liquid or gas from the respectivecontainer; a connection between the two plungers wherein the twoplungers are connected so that the liquid and gas from the respectivecontainers are moved simultaneously, fluid connections for connectingeach of the two containers to a contrast pattern generating chamber,wherein the gas and liquid form a gas-liquid composition having amultiply repeating pattern of discrete, alternating pattern of a gasphase and a liquid phase, to a catheter assembly comprising a catheterdelivery end positioned at or near a structure to be visualized; to theat least one fallopian tube to be visualized; and b) viewing the atleast one fallopian tube by sonography.
 26. The method of claim 25,wherein the device further comprises a pump drive attached to theconnection between the two plungers or to each of the two plungers in asimultaneous fashion.
 27. The method of claim 25, wherein the liquidfurther comprises one or more of a surfactant, emulsifier, stabilizingor dispersing agents.
 28. The method of claim 27, wherein thesurfactant, emulsifier, stabilizing or dispersing agent comprises one ormore of a tenside, a lecithin; phosphatidyl-choline; an ester or etherof fatty acids and fatty alcohols with polyoxyethylene; polyoxyethylatedpolyols; sorbitol, glycols and glycerol, cholesterol;polyoxy-ethylene-polyoxypropylene polymers, viscosity raising andstabilizing compounds, mono- and polysaccharides, glucose, lactose,sucrose, dextran; glycerol, polyglycols; and polypeptides; proteins,gelatin, oxypolygelatin, plasma protein, amphipathic compounds capableof forming stable films in the presence of water and gases;phospholipids, phosphatidic acid (PA), phosphatidylinositol,phosphatidylethanolamine (PE), phosphatidylserine (PS),phosphatidylglycerol (PG), cardiolipin (CL), sphingomyelins, aplasmogen, a cerebroside, egg lecithin or soya bean lecithin, orsynthetic lecithins; dimyristoylphosphatidylcholine,dipalmitoylphosphatidylcholine; distearoylphosphatidylcholine;unsaturated synthetic lecithins, dioleylphosphatidylcholine,dilinoleylphosphatidylcholine, free fatty acids, esters of fatty acidswith polyoxyalkylene compounds; polyoxypropylene glycol; polyoxyalkyleneglycol; ethers of fatty alcohols with polyoxyalkylene glycols; esters offatty acids with polyoxyalklated sorbitan; soaps; glycerol-polyalkylenestearate; glycerol-polyoxyethylene ricinoleate; homo- and copolymers ofpolyalkylene glycols; polyethoxylated soya-oil and castor oil orhydrogenated derivatives of polyethoxylated soya-oil and castor oil;ethers and esters of sucrose with fatty acids or fatty alcohols,polyoxyalkylated ethers and esters of sucrose with fatty acids or fattyalcohols; mono-di- and triglycerides of saturated or unsaturated fattyacids; glycerides of soya-oil and sucrose, block copolymers ofpolyoxypropylene and polyoxyethylene (poloxamers),polyoxyethylenesorbitans, glycerol-polyalkylene stearate,glycerolpolyoxyethylene ricinoleate, homo- and copolymers ofpolyalkylene glycols, glycerides of soya-oil, dextran, sucrose andcarbohydrates; polymerizable amphiphilic compounds of linoleyl-lecithinsor polyethylene dodecanoate, phosphatidic acid, phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol,phosphatidylinositol, cardiolipin, sphingomyelin; phosphatidylcholine(PC) dioleylphosphatidylcholine; dimyristoylphosphatidylcholine (DMPC),dipentadecanoylphosphatidylcholine-, dilauroylphosphatidylcholine(DLPC); dipalmitoylphosphatidylcholine (DPPC);disteraoylphosphatidylcholine (DSPC); diarachidonylphosphatid-ylcholine(DAPC); phosphatidylethanolamines (PE), dioleylphosphatidylethanolamine,dipaimitoylphosphatidylethanolamine (DPPE)distearoylphosphatidylethanolamine (DSPE); phosphatidylserine (PS),dipalmitoyl phosphatidylserine (DPPS), disteraoylphosphatidylserine(DSPS); phosphatidylglycerols (PG), dipalmitoylphosphatidylglycerol(DPPG), distearoylphosphatidylglycerol (DSPG); or phosphatidylinositol.29. The method of claim 25, wherein the liquid is water; a physiologicalelectrolyte solution, a physiological saline solution, Ringer'ssolution, an aqueous solution of sodium chloride, calcium chloride,sodium bicarbonate, sodium citrate, sodium acetate, or sodium tartrate;a glucose solution, a solutions of mono- or polyhydric alcohol, ethanol,n-butanol, ethylene glycol, polyvinylpyrrolidone, a physiologicallyacceptable non-aqueous solution, an anhydrous or substantially anhydrouscarrier liquid, a solution of an alcohol, a glycol, a polyglycol, asynthetic perfluoranated hydrocarbon, or mixtures or combinations ofnon-aqueous or aqueous liquids.
 30. The method of claim 25, wherein atleast one container is prefilled.
 31. The method of claim 25, whereinboth containers are prefilled.
 32. The device of claim 25, wherein thegas-liquid contrast medium composition further comprises a therapeuticagent, comprising, methotrexate, hormones, fertility enhancingcompounds, fertility interfering compounds, motility enhancingcompounds, motility interfering compounds, compounds affecting thecilia/deciliation cycle, cilia growth enhancing or interferingcompounds, ovarian follicle treatment compounds, antibacterial,antimicrobial, antifungal, antiviral, antimycoplasmal, or antiparisitalcompounds, compounds that reduce inflammation or scar tissue formation,one or more antibiotics, mucoproteins, electrolytes or enzymes toenhance or inhibit fertility, progesterone, estrogen, adrenergic activecompounds, noradrenergic active compounds, nonsteroidalanti-inflammatory drug, prostaglandins, hormones for fertility,fertility enhancing compounds, gametes, sperm, ova, combinations ofsperm and ova, one or more zygotes, or one or more embryos, orcombinations thereof.
 33. The device of claim 25, wherein the gascomprises air, carbon dioxide, oxygen, nitrogen, halocarbon compoundgases, or a known contrast agent gas.
 34. A method of treating a uterusor at least one fallopian tube, or both, comprising, a) providing agas-liquid composition comprising a liquid comprising at one therapeuticagent and a gas, that is made by a liquid and gas contrastmedium-forming device comprising a container assembly comprising twocontainers having the same volume, a first container for containing agas and a second container for containing a liquid, two plungers, eachdisposed in a respective container, each for moving a liquid or gas fromthe respective container; a connection between the two plungers whereinthe two plungers are connected so that the liquid and gas from therespective containers are moved simultaneously, fluid connections forconnecting each of the two containers to a contrast pattern generatingchamber, wherein the gas and liquid form a gas-liquid composition havinga multiply repeating pattern of discrete, alternating pattern of a gasphase and a liquid phase, to a catheter assembly comprising a catheterdelivery end positioned at or near the uterus or at least one fallopiantube, or both, to be treated; and b) contacting the uterus or at leastone fallopian tube, or both, with the gas-liquid composition to providean effective amount of the at least one therapeutic agent to the uterusor at least one fallopian tube, or both.
 35. The method of claim 34,wherein two fallopian tubes are treated.
 36. The method of claim 34,wherein the uterus is treated.
 37. The method of claim 34, wherein thedevice further comprises a pump drive attached to the connection betweenthe two plungers or to each of the two plungers in a simultaneousfashion.
 38. The method of claim 34, wherein the liquid furthercomprises one or more of a surfactant, emulsifier, stabilizing ordispersing agents.
 39. The method of claim 38, wherein the surfactant,emulsifier, stabilizing or dispersing agent comprises one or more of atenside, a lecithin; phosphatidyl-choline; an ester or ether of fattyacids and fatty alcohols with polyoxyethylene; polyoxyethylated polyols;sorbitol, glycols and glycerol, cholesterol;polyoxy-ethylene-polyoxypropylene polymers, viscosity raising andstabilizing compounds, mono- and polysaccharides, glucose, lactose,sucrose, dextran; glycerol, polyglycols; and polypeptides; proteins,gelatin, oxypolygelatin, plasma protein, amphipathic compounds capableof forming stable films in the presence of water and gases;phospholipids, phosphatidic acid (PA), phosphatidylinositol,phosphatidylethanolamine (PE), phosphatidylserine (PS),phosphatidylglycerol (PG), cardiolipin (CL), sphingomyelins, aplasmogen, a cerebroside, egg lecithin or soya bean lecithin, orsynthetic lecithins; dimyristoylphosphatidylcholine,dipalmitoylphosphatidylcholine; di stearoylphosphatidylcholine;unsaturated synthetic lecithins, dioleylphosphatidylcholine,dilinoleylphosphatidylcholine, free fatty acids, esters of fatty acidswith polyoxyalkylene compounds; polyoxypropylene glycol; polyoxyalkyleneglycol; ethers of fatty alcohols with polyoxyalkylene glycols; esters offatty acids with polyoxyalklated sorbitan; soaps; glycerol-polyalkylenestearate; glycerol-polyoxyethylene ricinoleate; homo- and copolymers ofpolyalkylene glycols; polyethoxylated soya-oil and castor oil orhydrogenated derivatives of polyethoxylated soya-oil and castor oil;ethers and esters of sucrose with fatty acids or fatty alcohols,polyoxyalkylated ethers and esters of sucrose with fatty acids or fattyalcohols; mono-di- and triglycerides of saturated or unsaturated fattyacids; glycerides of soya-oil and sucrose, block copolymers ofpolyoxypropylene and polyoxyethylene (poloxamers),polyoxyethylenesorbitans, glycerol-polyalkylene stearate,glycerolpolyoxyethylene ricinoleate, homo- and copolymers ofpolyalkylene glycols, glycerides of soya-oil, dextran, sucrose andcarbohydrates; polymerizable amphiphilic compounds of linoleyl-lecithinsor polyethylene dodecanoate, phosphatidic acid, phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol,phosphatidylinositol, cardiolipin, sphingomyelin; phosphatidylcholine(PC) dioleylphosphatidylcholine; dimyristoylphosphatidylcholine (DMPC),dipentadecanoylphosphatidylcholine-, dilauroylphosphatidylcholine(DLPC); dipalmitoylphosphatidylcholine (DPPC);disteraoylphosphatidylcholine (DSPC); diarachidonylphosphatid-ylcholine(DAPC); phosphatidylethanolamines (PE), dioleylphosphatidylethanolamine,dipaimitoylphosphatidylethanolamine (DPPE)distearoylphosphatidylethanolamine (DSPE); phosphatidylserine (PS),dipalmitoyl phosphatidylserine (DPPS), disteraoylphosphatidylserine(DSPS); phosphatidylglycerols (PG), dipalmitoylphosphatidylglycerol(DPPG), distearoylphosphatidylglycerol (DSPG); or phosphatidylinositol.40. The method of claim 34, wherein at least one container is prefilled.41. The method of claim 34, wherein both containers are prefilled. 42.The method of claim 34, wherein the gas-liquid contrast mediumcomposition comprises a therapeutic agent comprising methotrexate,hormones, fertility enhancing compounds, fertility interferingcompounds, motility enhancing compounds, motility interfering compounds,compounds affecting the cilia/deciliation cycle, cilia growth enhancingor interfering compounds, ovarian follicle treatment compounds,antibacterial, antimicrobial, antifungal, antiviral, antimycoplasmal, orantiparisital compounds, compounds that reduce inflammation or scartissue formation, one or more antibiotics, mucoproteins, electrolytes orenzymes to enhance or inhibit fertility, progesterone, estrogen,adrenergic active compounds, noradrenergic active compounds,nonsteroidal anti-inflammatory drug, prostaglandins, hormones forfertility, fertility enhancing compounds, gametes, sperm, ova,combinations of sperm and ova, one or more zygotes, or one or moreembryos, or combinations thereof.
 43. The method of claim 34, whereinthe gas comprises air, carbon dioxide, oxygen, nitrogen, halocarboncompound gases, or a known contrast agent gas.
 44. The method of claim34, wherein the liquid is water; a physiological electrolyte solution, aphysiological saline solution, Ringer's solution, an aqueous solution ofsodium chloride, calcium chloride, sodium bicarbonate, sodium citrate,sodium acetate, or sodium tartrate; a glucose solution, a solutions ofmono- or polyhydric alcohol, ethanol, n-butanol, ethylene glycol,polyvinylpyrrolidone, a physiologically acceptable non-aqueous solution,an anhydrous or substantially anhydrous carrier liquid, a solution of analcohol, a glycol, a polyglycol, a synthetic perfluoranated hydrocarbon,or mixtures or combinations of non-aqueous or aqueous liquids.